Gaucher disease is a lysosomal storage disorder that is associated with the accumulation of glycosphingolipids (GSL) in cells, particularly monocytes and macrophages, of afflicted individuals. This aberrant build up of GSL results from a genetic deficiency (mutation) in the gene encoding the lysosomal enzyme acid β-glucosidase (glucocerebrosidase; GCase), the lysosomal hydrolase that breaks down the GSL glucosylceramide (GluCer). The majority of glucocerebrosidase gene (Gba) mutations cause the GCase protein to misfold in the endoplasmic reticulum (ER). Misfolded GCase is recognized by the ER quality control system and subsequently degraded instead of being processed and trafficking to the lysosome.
Gaucher disease is pan-ethnic, with an overall disease frequency of about 1 in 50,000-100,000 births. Certain populations have a higher prevalence. In the Ashkenazi population, for example, about 1 in 15 people are carriers for a Gba mutation. According to the National Gaucher Foundation, about 2,500 Americans suffer from Gaucher disease.
Gaucher disease is an autosomal recessive disorder and is the most common lysosomal storage disease. The disease has been classified into three clinical types, depending on neurological involvement and disease severity. Type 1 is the most common and is characterized by an absence of neurological involvement. Patients exhibit a broad spectrum of severity; some can remain asymptomatic throughout life. Most Type 1 patients exhibit enlargement of the spleen and liver, skeletal abnormalities and bone lesions, and sustained inflammatory reactions. Hepatic glucocerebroside levels are elevated from 23-fold to 389-fold above normal levels in Type 1 Gaucher patients.
Type 2 Gaucher disease is the rarest and most severe form. It is associated with early onset of acute neurologic disease. The characteristic feature of neuronopathic Gaucher disease is an abnormality of horizontal gaze. Afflicted patients develop progressive encephalopathy and extrapyrimidal symptoms such as rigidity and Parkinson's-like movement (parkinsonism). Most Type 2 Gaucher patients die in early childhood from apnea or aspiration due to neurological deterioration.
Type 3 Gaucher disease also has neurological involvement, although to a lesser extent than Type 2. These patients also have the hepatosplenomegaly and skeletal defects characteristic of Type 1, as well as central nervous system symptoms that include poor coordination of movements (ataxia), seizures, paralysis of the eye muscles, epilepsy, and dementia. Patients with Type 3 Gaucher disease can live into adulthood, but may have a shortened life span. Three sub-classifications of Type 3 have been reported: Type 3a, which is associated with prominent hepatosplenomegaly and bone marrow disease; Type 3b, which is associated with limited systemic symptoms; and Type 3c, which is associated with hepatosplenomegaly, corneal opacities, progressive ataxia and dementia, and cardiac valve and aortic root calcification.
Approaches for the treatment of Gaucher disease include enzyme replacement therapy (ERT), bone marrow transplants (BMT), substrate reduction therapy (SRT), gene therapy, and pharmacological chaperone treatment. Isofagomine is a potent inhibitor of recombinant human acid β-glucosidase (GCase). Pharmacological chaperone methods for enhancing mutant enzyme activities in lysosomal storage disorders using enzyme inhibitors such as isofagomine are disclosed in commonly owned U.S. Pat. Nos. 6,916,829; 6,599,919; 6,589,964; 6,583,158, and 7,141,582 each of which are herein incorporated by reference in their entirety. For example, the addition of an inhibitor of GCase to a fibroblast culture medium has been shown to lead to an increase in the trafficking and lysosomal activity of GCase, indicating that such an inhibitor may be of therapeutic interest in the treatment of Gaucher disease.
It has recently been discovered that there is a link between mutations in the Gba gene and Parkinson's disease. In one study, a group of 17 patients with rare, early onset, treatment-resistant parkinsonism were found to have at least one allele with a Gba missense mutation, including homozygous and heterozygous individuals for N370S, a mutation typically associated with type 1, non-neuronopathic disease (Tayebi et al., Mol. Genet. Metab. 2003; 79; 104-109). In another study, a population of 99 Ashkenazi Jews with idiopathic Parkinson's disease were evaluated for six Gba mutations (N370S, L444P, 84GG, V394L, and R496H). Thirty-one Parkinson's patients had one or two mutant Gba alleles: 23 were heterozygous for N370S; 3 were homozygous for N370S; 4 were heterozygous for 84GG; and 1 was heterozygous for R496H (Aharon-Peretz et al., New Eng. J. Med. 2004; 351: 1972-77). The frequency of a mutant N370S allele was 5 times that among 1573 normal subjects, and that of 84GG was 21 times that of normal subjects. Among patients with Parkinson's disease, patients carrying a Gba mutation also were younger than those who were not carriers. This study suggests that heterozygosity for a Gba mutation may predispose Ashkenazi Jews to Parkinson's disease. Since isofagomine has been shown to cross the blood-brain barrier in animals, and increases the activity of both mutant wild-type GCase, it can be used to treat both Parkinson's patients who have a heterozygous mutation in GCase, or who are at risk for developing Parkinson's disease due to other factors, but who may benefit from increased levels of wild-type GCase.
Although the compound of isofagomine is a potent and selective recombinant human acid β-glucosidase (GCase) inhibitor, its use in pharmaceutical products presents challenges. For example, the hydrochloride salt of isofagomine (isofagomine-HCl) is disclosed in U.S. Pat. No. 5,844,102. However, isofagomine-HCl as well as isofagomine free base are not readily purified on a large scale and have poor solid state properties for use in an industrial scale manufacturing processes and pharmaceutical formulations.